EDUCATION CLINICAL REVIEW

Sepsis in children
• Link to this article online
for CPD/CME credits Adrian Plunkett,1 Jeremy Tong2

1
Birmingham Children’s Hospital, Sepsis is a clinical syndrome resulting from a dysregulated
Birmingham, UK systemic inflammatory response to infection.1 It is charac-
2
University Hospitals of Leicester
terised by a generalised pro-inflammatory cascade, which
NHS Trust, Leicester, UK
Correspondence to: A Plunkett
may lead to widespread tissue injury.2 It encompasses a
adrian.plunkett@bch.nhs.uk clinical spectrum of severity, including severe sepsis, septic
Cite this as: BMJ 2015;350:h3017 shock, and multi-organ failure.3 Sepsis is a leading cause of
doi: 10.1136/bmj.h3017 morbidity and mortality in children worldwide.4
The aim of this review is to provide an overview of the
This clinical review has been
developed for The BMJ in causes, diagnosis, and current management of sepsis in
collaboration with BMJ Best
children.
Practice, based on a regularly
updated web/mobile topic that
supports evidence-based decision What is the epidemiology?
making at the point of care. To Global data on sepsis in children are incomplete, but it is esti-
view the complete and current
version, please refer to the Sepsis
mated that infection accounts for most deaths (almost 60%)
in children (http://bestpractice. in children aged under 5 years.4
bmj.com/best-practice/ The World Health Organization has stated that the four big
monograph/1201.html) topic on
the BMJ Best Practice website.
causes of death in children worldwide are infectious diseases:
pneumonia (1.9 million deaths/year), diarrhoea (1.6 million
deaths/year), malaria (1.1 million deaths/year), and measles
(550 000 deaths/year).6
The largest epidemiological reports of the incidence of
severe sepsis in children come from US cohort studies.7  8 These
studies show a rising annual incidence of severe sepsis (0.56
This is an edited version of the to 0.89 cases/1000 children, across all age groups).8 The inci-
clinical review. The full version is dence of severe sepsis in these cohorts was significantly higher
on thebmj.com
in younger age groups (incidence in the neonatal age group
and infants aged <1 year was 9.7 and 2.25 cases per 1000
children, compared with 0.23 to 0.52 in children aged 1 to 19
years). Severe sepsis was also more common in children with
comorbidities. Despite the rising incidence of severe sepsis, the
case fatality rate has fallen from 10.3% to 8.9%.8
What causes sepsis?
While any infection may precipitate sepsis, the most common
pathogens are bacteria, viruses, and fungi. The type of patho-
gen varies according to host factors, including age, comorbid-
ity, and geographic location. Typical or important pathogens
by patient group are listed in box 1.7  11‑ 14
Sepsis occurs when the normal, pro-inflammatory host
response to infection exceeds its usual homeostatic constraints
THE BOTTOM LINE
• The initial clinical presentation of sepsis in children may be non-specific (especially
in younger age groups)
• Given the time critical nature of severe sepsis and septic shock, when sepsis
is suspected on clinical grounds it is usually best to start investigations and
treatment for sepsis, including fluid resuscitation, and to continue with these until
sepsis has been excluded
• Progression to organ failure and shock is often rapid, so early recognition and
treatment are crucial
• Apart from antibiotics, there are currently no specific treatments of proved value
• Other treatment after antibiotics is supportive and should be delivered according
to internationally recognised, consensus based guidelines
SOURCES AND SELECTION CRITERIA
We searched Medline and Embase from October 2008 to
October 2013 and the Cochrane Library to issue September
2013 (online) for systematic reviews and randomised
controlled trials (any size) on treatment, prevention,
and diagnosis and searched specified websites for
guidelines using the terms sepsis, severe sepsis, septic
shock, paediatric, children. Our search was updated in
January 2015. Additional data sources came from authors’
institutional guildelines and policies.
and becomes a generalised process, resulting in inflammation
remote from the infection source.
While this model of sepsis is intuitive, the results of
emerging research suggest that it may be an oversimpli-
fication and that the pathophysiology includes processes
such as endothelium dysfunction, cell death, bioenergetic
derangement, and immunoparalysis.
Can sepsis be prevented?
Primary prevention
The principal method of primary prevention is immuni-
sation. Advances in biotechnology have led to new and
improved vaccines, including vaccines for Haemophilus
influenzae type b, Neisseria meningitides (type C), and
Streptococcus pneumoniae.20
A new group B meningococcal vaccine has been licensed
in Europe. In 2015, the meningococcal B vaccine will be
introduced to the routine childhood vaccination pro-
gramme in the UK.21
Primary prevention is also relevant with healthcare
associated infections. Since these infections are related to
specific interventions (such as insertion of a vascular cath-
eter), there are opportunities to reduce the risk of infection
through improvements in clinical practice (such as improved
handwashing practices, protective isolation, and universal
precautions).
Screening
Screening for sepsis in the asymptomatic population is not
useful. However, screening for maternal colonisation with
group B streptococci in pregnancy has been shown in some
settings to reduce the burden of group B streptococci disease
in newborns.
Secondary prevention
Long term antimicrobial prophylaxis with antibiotics, antivi-
rals, or antifungals is recommended in immunocompromised
patients with premorbid conditions (such as leukaemia). Chil-
dren with cystic fibrosis and other respiratory diseases may
be given antimicrobial prophylaxis (such as co-trimoxazole).
How is sepsis diagnosed?
Sepsis should be considered as a time critical emergency, as

the bmj | 13 June 2015 27

EDUCATION CLINICAL REVIEW
Box 1 | Typical or important pathogens in sepsis
Early onset neonatal sepsis
Defined as neonatal sepsis occurring in the first 72 hours of life15
• Group B streptococci, and Gram negative bacilli (especially Escherichia coli)
• Staphylococcus aureus and coagulase negative staphylococci, Haemophilus influenzae, and
enterococci
• Listeria monocytogenes (rare)
Late onset neonatal sepsis
Defined as neonatal sepsis occurring after the first 72 hours to one month of life18
• Coagulase negative staphylococci (common cause owing to the high incidence in vascular
catheter associated infection in neonatal inpatients)
• May also be caused by the same organisms responsible for early onset neonatal sepsis
Infants and young children
• Streptococcus pneumoniae
• Neisseria meningitidis (occurs in a bimodal age distribution, affecting young children and
adolescents)
• S aureus and group A streptococci
• Haemophilus influenzae type b (important cause of sepsis worldwide, but it is rare in the
developed world because of vaccination)
• Bordetella pertussis (although rare, may cause a severe illness in young infants before primary
vaccination)
• In resource poor settings diarrhoea and pneumonia are the most common infections (and
causes of death)4
Infants and children in hospital
• Cause of hospital acquired infection depends on local bacterial epidemiology
• Coagulase negative staphylococci are usually associated with vascular catheter infection
• Meticillin resistant Staphylococcus aureus (MRSA)
• Gram negative organisms such as Pseudomonas aeruginosa, Klebsiella species, E coli, and
Acinetobacter species.
Asplenic or functional asplenia
• Salmonella sepsis, including salmonella osteomyelitis in sickle cell disease
• Other encapsulated organisms (for example, Streptococcus pneumoniae, Haemophilus
influenzae)
Mosquito-borne disease
• Malaria (Plasmodium falciparum), dengue virus, and Burkholderia pseudomallei (meliodosis)
Other organisms
Fungal (for example, Candida species, Aspergillus species) and viral (for example, influenza,
respiratory syncytial virus, human metapneumovirus, varicella, and herpes simplex virus)
pathogens account for as many as 5.3% and 2.9% of severe sepsis in children, respectively8
the disease may progress rapidly to organ failure, shock, and
death. Prompt and early recognition of the condition is there-
fore imperative. In general, sepsis should be suspected in any
acute illness or in the neonatal population (including preterm
infants) if there is any change from the patient’s normal pat-
tern of observations.
While laboratory tests (such as blood cultures and biomark-
ers) are helpful in securing or supporting the diagnosis, the
diagnosis has to be made initially using clinical judgment.
When sepsis is suspected it is usually best to initiate sepsis
investigations and treatment and to continue until sepsis has
been excluded.
Clinical features of sepsis
The typical presentation varies according to the age of the
child. Whereas older children may present with a focus of
infection, infants and neonates usually present with non-
specific symptoms and signs. In older infants and chil-
dren, sepsis typically presents with features of systemic
inflammatory response syndrome (defined in box 2), the
most common feature of which is fever.3
28 13 June 2015 | the bmj
In practice, the clinician should consider sepsis or septic
shock if a child has a suspected or proved infection and has
at least two of the following:
•   Core temperature <36°C or >38.5°C (<97°F or >101°F)
•   Inappropriate tachycardia (according to local criteria or
advanced paediatric life support guidance)
•    ltered mental state (such as sleepiness, irritability,
A
lethargy, floppiness)
•   Reduced peripheral perfusion or prolonged capillary
refill.
If in doubt, an experienced paediatrician should be con-
sulted.30
In neutropenic patients sepsis should be considered if the
core temperature is >38°C (>100°F).
In all age groups, if sepsis has progressed, the patient
may develop severe sepsis or septic shock. Septic shock
may manifest in two main clinical pictures: cold shock and
warm shock (box 3 see thebmj.com). In both shock states,
the patient will show clinical signs of shock outside the car-
diovascular system, the most important of which is impaired
neurological function. This may manifest as irritability,
apnoeas and drowsiness, obtundation, or delirium.
Children often maintain normal blood pressure even in late
stages of shock; therefore, hypotension is often a terminal sign.
Purpura fulminans is a widespread non-blanching purpu-
ric rash classically seen in meningococcaemia.
Decreased urine output is common in acutely ill children
and often reflects a degree of dehydration (due to decreased
intake, excessive fluid losses, or both). This is not a specific
finding in sepsis.
The UK based National Institute of Health and Care Excel-
lence (NICE) has developed a traffic light system based on
clinical signs, which helps physicians assess the probability
of serious illness in young children presenting with fever
(www.nice.org.uk/guidance/cg160/resources/cg160-fever-
ish-illness-in-children-support-for-education-and-learning-
educational-resource-traffic-light-table2).
How is sepsis managed?
Management of sepsis in children first requires prompt rec-
ognition. A standard ABC (airway, breathing, circulation)
approach with particular emphasis on early administration
of antibiotics and fluid resuscitation is key in children with
sepsis and septic shock.
Treatment according to American College of Critical Care
Medicine guidelines and bundles
Compliance with guidelines or care bundles is associated with
improved outcomes.43
One study in the tertiary accident and emergency depart-
ment at Boston Children’s Hospital looked at delivery of care.
Those who received the care bundle recommended by the
American College of Critical Care Medicine44 guidelines (early
recognition of severe sepsis, vascular access, antibiotic admin-
istration, administering intravenous fluids, and vasopressors
for fluid refractory shock) had a significantly shorter intensive
care length of stay (mean 5.5 v 6.8 days) and hospital length
of stay (mean 6.8 v 10.9 days).
Adherence to all five elements of care in this study was low
at 19%. In a UK pre-intensive care unit audit, adherence to
the ACCM-PALS guideline was only 38%.46 Reasons for poor

Box 2 | Definitions for sepsis in children* (from the International Consensus Conference on
Pediatric Sepsis3)
Infection
Suspected or proved infection with any pathogen
Systemic inflammatory response syndrome
Generalised inflammatory response, defined by the presence of ≥2 of the following criteria
(abnormal temperature or white cell count must be one of the criteria):
––Abnormal core temperature (<36°C or >38.5°C)
––Abnormal heart rate (>2 standard deviations above normal for age, or <10th centile for age if
child is aged <1 year)
––Raised respiratory rate (>2 standard deviations above normal for age, or mechanical
ventilation for acute lung disease)
––Abnormal white cell count in circulating blood (above or below normal range for age, or
>10% immature white cells)
Sepsis
Systemic inflammatory response syndrome in the presence of infection
Severe sepsis
Sepsis in the presence of cardiovascular dysfunction, acute respiratory distress syndrome, or
dysfunction of ≥2 organ systems
Septic shock
Sepsis with cardiovascular dysfunction persisting after at least 40 mL/kg of fluid resuscitation in
one hour
Refractory septic shock
Fluid refractory septic shock—Shock persisting after ≥60 mL/kg of fluid resuscitation
Catecholamine resistant septic shock—Shock persists despite treatment with catecholamines
*The following standardised definitions were initially developed by the International Consensus
Conference on Pediatric Sepsis to standardise entry criteria for large multicentre clinical trials.
Clinical diagnosis of sepsis must occur earlier in the care pathway than classification allows
compliance are multifactorial.47 The same team at Boston
Children’s Hospital subsequently reported improvement
in compliance 19% to 100% using process focused quality
improvement methodology. They observed a reduction in
mortality from 4.8% to 1.7%.48
The Surviving Sepsis Campaign (SSC) (www.
survivingsepsis.org/Pages/default.aspx) suggests mak-
ing systems change within institutions through incre-
mental steps. The SSC bundles are available here. (www.
survivingsepsis.org/Bundles/Pages/default.aspx).
Paediatric Sepsis Six initiative
Developed by the UK Sepsis Trust Paediatric Group, the Paedi-
atric Sepsis Six is modelled on the adult Sepsis Six programme
that has been shown to improve adherence to resuscitation
bundles and early goal directed therapy guidelines, and is
associated with reduced mortality.31
The Paediatric Sepsis Six does not replace existing ACCM-
PALS guidance; it is an operational solution to improve adher-
ence to the guideline. It is designed to empower medical and
nursing staff to recognise sepsis early and initiate treatment
rapidly. The following interventions should be initiated within
1 hour of presentation:
•   Supplemental oxygen should be given
•   Intravenous or intraosseous access should be obtained
and blood tests ordered including blood cultures, blood
glucose (low blood glucose should be treated), and blood
gases. Full blood count, serum lactate, and C reactive
protein should also be ordered
•   Intravenous or intraosseous antibiotics should be given
with broad spectrum cover as according to local policies
•   Fluid resuscitation should be considered. The aim is to
the bmj | 13 June 2015 29
EDUCATION CLINICAL REVIEW
restore normal circulating volume and physiological
parameters. Isotonic fluid (20 mL/kg) should be titrated
over 5 minutes and repeated as necessary. Caution
should be taken to avoid fluid overload by examining for
crepitations (rales) and hepatomegaly
•   Experienced senior clinicians or specialists should be
involved and consulted early
•   Vasoactive-inotropic support should be considered early
if normal physiological parameters are not restored after
giving ≥40 mL/kg of fluids. Adrenaline (epinephrine) or
dopamine may be given via peripheral intravenous or
intraosseous access.
Airway and respiratory support
The airway and breathing should be managed as in advanced
life support and resuscitation algorithms.
Oxygen should be titrated according to pulse oximetry,
aiming for an oxygen saturation of >94% once the patient is
haemodynamically stable. Caution should be exercised in pre-
mature neonates or neonates suspected of having congenital
heart disease.
Intubation is recommended if respiratory support is
required or for patients with a reduced level of consciousness.
The clinician should be prepared for cardiovascular collapse
or cardiac arrest on induction of anaesthesia for intubation.
Initial fluid resuscitation
Profound fluid loss from the intravascular space occurs
owing to capillary leak and may persist for several days.
The key is rapid early infusion, aiming to restore normal
physiological parameters of heart rate and blood pressure.44
The choice of fluid is less important, provided it is isotonic.
Crystalloids such as sodium chloride (0.9%) and compound
sodium lactate (Hartmann’s solution or lactated Ringer’s solu-
tion) are commonly used and are appropriate; albumin (4.5%)
may also be used. There could be theoretical advantages in
using colloids for resuscitation in children with sepsis, but
colloids are not favoured in adult resuscitation,49 and there is
insufficient evidence to make a recommendation for or against
colloids in children.50 51
Fluids should be administered only in the absence of signs
of fluid overload (that is, increased work of breathing, pulmo-
nary crepitations, hepatomegaly, gallop rhythm). It would not
be unusual for a child in septic shock to receive >100 mL/kg
of fluid resuscitation within the first 24 hours of admission,
due to fluid maldistribution, but vasoactive-inotropic support
should also be considered early in fluid refractory shock.
Antibiotic therapy
Early administration of antibiotics saves lives. In adults, a
study has shown that for every hour of delay in starting anti-
biotics in septic shock, there is an associated 7.6% increase
in mortality.53 There are only a few similar studies in children,
but there is compelling evidence that early antibiotic admin-
istration saves lives in children as well. In a retrospective study
of 80 children, those who received antibiotics within 1 hour
of admission were observed to have significantly lower lev-
els of serum lactate and C reactive protein within the first 24
hours of admission. Although the study was underpowered
to detect a change in mortality, the time to reversal of shock in
children who received antibiotics within an hour was signifi-
 EDUCATION CLINICAL REVIEW

Box 4 | Diagnostic tests for sepsis (for full explanation see box online)
First tests to order
Full blood count with differential
Serum glucose
Blood culture
Blood culture results should be reviewed every 12 to 24 hours; most positive
results will be detectable within 48 hours, and many will be positive within 24
hours.35
Urine analysis and urine culture—Urine analysis (urine sample for nitrites,
microscopy, Gram stain, and culture) should be considered in all neonates with
sepsis (although in the first week of life, a positive result in urine culture may
simply reflect a severe bacteraemia). It should be considered in older children
with symptoms suggestive of a urinary tract infection. Urine analysis may not be
possible until after fluid resuscitation.
Blood gases—Although children rarely have arterial blood gases taken in
the emergency department, it is often possible to obtain clinically useful
information from capillary or venous blood gases.
Serum lactate—Lactate is most reliably assessed using an arterial sample;
venous and capillary lactate should be interpreted with caution.
Serum electrolytes—Should be measured at baseline and regularly until patients
improve.
Serum creatinine—Increased serum creatinine is indicative of sepsis related
renal failure.3
Liver function tests—Increased bilirubin levels (outside the neonatal age range)
or increased alanine aminotransferase is suggestive of sepsis related liver
dysfunction.3
Coagulation studies—In the context of sepsis and thrombocytopenia, abnormal
results are indicative of disseminated intravascular dissemination.3  36
C reactive protein—May be useful for the diagnosis and monitoring of sepsis and
septic shock. Current practice varies regarding the use of C reactive protein, and
clinicians should continue to use clinical judgment.
Chest radiography—Infants and small children with respiratory distress in the
context of suspected sepsis should undergo chest radiography to assess for
pneumonic changes.
Tests to consider
Lumbar puncture—Lumbar puncture is usually contraindicated in children with
severe sepsis until the patient is stabilised, as performing a lumbar puncture in
severe sepsis may lead to collapse.
Meningococcal polymerase chain reaction (PCR) analysis—This may help
confirm the diagnosis in equivocal or suspected clinical cases of meningococcal
sepsis, but it is not widely available
Bronchoalveolar lavage culture—may be considered for a child in an intensive
care unit with a suspected ventilator associated pneumonia.
Herpes simplex virus PCR (blood and cerebrospinal fluid)—Neonatal herpes
simplex infection (either in the central nervous system or disseminated) is rare,
but an important consideration in children with severe sepsis.
Emerging tests
Serum procalcitonin—This biomarker may be useful for the diagnosis
and monitoring of sepsis and septic shock, but the test is not commonly
available. It not currently considered to be the standard of care in the UK or
Europe.
Emerging biomarkers—Other biomarkers (such as CD64, interleukin 18, mass
spectrometry, specific mRNA expression) are considered emerging and are not
widely used or validated yet.

The full disclaimer applicable to
BMJ Best Practice can be found at
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practice/marketing/disclaimer.html.
Contributors: AP (guarantor):
wrote the sections on introduction,
epidemiology, pathophysiology and
causes, prevention, and diagnosis. JT
wrote the sections on management,
complications, and prognosis.
Competing interests: We have read
and understood the BMJ policy on
declaration of interests and declare
the following interests: AP and JT are
involved in the Paediatric Sepsis Six
initiative.
Provenance and peer review:
Commissioned; externally peer
reviewed.
cantly shorter.54 Another retrospective study of 130 children
with sepsis or septic shock reported an increase in the odds
ratio (3.92) for mortality in a paediatric intensive care unit in
children who received antibiotics more than 3 hours from rec-
ognition of sepsis (odds ratio 4.84 after adjusting for severity
of illness).55
The choice of antibiotic is complex and should be based
on the clinical syndrome, underlying disease, drug intoler-
ances, and local pathogen susceptibility. Treatment should
be initiated with broad spectrum antibiotic cover. This can be
changed to an appropriate narrow spectrum antibiotic regi-
men once a causative pathogen is identified.
It is good practice to review antibiotic therapy on a daily
basis for clinical effect and de-escalate when appropriate. A
5-7 day course of intravenous antibiotics would suffice in most
uncomplicated infections.
An infectious disease specialist should be consulted if there
are any unusual features to the case, or for advice on appropri-
ate antimicrobial choice and length of treatment if the clinical
condition is not improving.
Antifungal and antiviral therapy
The practice of providing antifungal prophylaxis while giving
antibiotic therapy varies between institutions.
Blood transfusion
It is suggested a haemoglobin concentration of >10 g/dL
(approximate packed cell volume of 0.3) should be main-
tained. Once shock has resolved, a lower transfusion threshold
may be appropriate.
Corticosteroids
Evidence for the use of corticosteroids in severe sepsis and
septic shock has often been conflicting.61 The Surviving Sepsis
Campaign guidelines do not recommend routine use of hydro-
cortisone in adult severe sepsis but recommend it as an option
in the context of fluid refractory and inotrope resistant septic
shock. In children, there is limited evidence for the use of
hydrocortisone in fluid refractory and inotrope resistant shock
with suspected or proved absolute adrenal insufficiency.59  62
Special considerations for newborn septic shock
Any newborn presenting with signs of cardiogenic shock (such
as poor perfusion, cyanosis, heart murmur, hepatomegaly, dif-
ferential pulse volume, and limb pressure between upper and
lower limbs) should be started on a prostaglandin infusion
under expert guidance until a duct dependent cardiac lesion
can be ruled out.
Temperature control
Normothermia (36.5°C to 37.5°C (97.5°F to 99.5°F)) should
be maintained. External sources of heat may be required. Con-
versely, hyperthermia increases metabolic demand at any age,
and should be avoided.
What is the prognosis?
Without treatment, severe sepsis carries a mortality rate in
excess of 80%.68 With treatment, overall mortality is approxi-
mately 10% in children up to the age of 19 years.69 There is no
gender difference in children. Patients with pre-existing dis-
ease experience a higher mortality rate of 12.8% compared
with 7.8% in previously healthy children.70
Persistent shock on admission to an intensive care unit is
associated with an increased odds ratio for death of 3.8.45 The
complications of sepsis, their management and follow-up are
discussed in more detail online.

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